Unravelling the molecular mechanism of Sorcin (SOluble Resistance-related Calcium binding proteIN)-dependent resistance to chemotherapeutic drugs in cancer and its network of interaction

Sorcin is calcium-binding oncoprotein overexpressed in several human tumors, is a marker of Multi-Drug Resistance (MDR), is highly expressed in chemoresistant cell lines, and confers MDR when overexpressed. Sorcin gene is in the same amplicon of glycoprotein-P (mdr1) and its silencing increases cancer cell sensitivity to chemotherapeutic drugs. Recently we solved the crystal structure of Sorcin in the apo and calcium-bound forms. Upon calcium binding, a large conformational change occurs, with the exposure of hydrophobic surfaces, that allows Sorcin interaction with molecular targets, some of them unravelled by a cutting-edge technique called Proteomic Peptide Phage Display (ProPPD). To elucidate Sorcin-dependent chemoresistance mechanisms, we: - used H1299 lung cancer cells, which express high amount of Sorcin; - silenced Sorcin expression through siRNA; - treated cells with doxorubicin to elucidate changes in the uptake process and in the biological response; - tested Sorcin affinity for doxorubicin through Surface Plasmon Resonance and fluorimetry experiments; -solved the crystal structure of doxorubicin-bound Sorcin. Our results show that, by direct and specific binding of doxorubicin, Sorcin can act as a buffer for the drug in the cytoplasm, enhance its accumulation outside the nucleus and then its extrusion through MDR1 pump. Indeed Sorcin silencing, in our cancer cells, increases the sensitivity towards the chemotherapeutic drug and subsequently cell death upon treatment.